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bioRxiv · 10.1101/2021.02.25.432706

Intrinsic Gating Behavior of Voltage-Gated Sodium Channels Predetermines Regulation by Auxiliary β-subunits

Brake, N.·Mancino, A. S.·Yan, Y.·Shimomura, T.·Silveira, H.·Kubo, Y.·Khadra, A.·Bowie, D.
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Abstract

Voltage-gated sodium (Nav) channels mediate rapid millisecond electrical signaling in excitable cells. Auxiliary subunits, {beta}1-{beta}4, are thought to regulate Nav channel function through covalent and/or polar interactions with the channel s voltage-sensing domains. How these interactions translate into the diverse and variable regulatory effects of {beta}-subunits remains unclear. Here, we find that the intrinsic movement order of the voltage-sensing domains during channel gating is unexpectedly variable across Nav channel isoforms. This movement order dictates the channel s propensity for closed-state inactivation, which in turn modulates the actions of {beta}1 and {beta}3. We show that the differential regulation of skeletal muscle, cardiac, and neuronal Nav channels is explained by their variable levels of closed-state inactivation. Together, this study provides a unified mechanism for the regulation of all Nav channel isoforms by {beta}1 and {beta}3, which explains how the fixed structural interactions of auxiliary subunits can paradoxically exert variable effects on channel function.

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Brake, N., Mancino, A. S., Yan, Y., Shimomura, T., Silveira, H., Kubo, Y., Khadra, A., Bowie, D.. 2021-02-25. Intrinsic Gating Behavior of Voltage-Gated Sodium Channels Predetermines Regulation by Auxiliary β-subunits. https://doi.org/10.1101/2021.02.25.432706

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